Mechanism of host cell apoptosis inhibition by Mycobacterium tuberculosis

Univ Of Maryland, College Park, College Park MD

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Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infections, claims the lives of 2-[unreadable] 3 million people annually. The importance of the development of more efficient drugs and[unreadable] vaccines is reinforced by: the emergence of multi-drug resistant and extreme-drug resistant Mtb[unreadable] strains and secondly, the deadly synergism between the HIV/AIDS epidemic and TB due to[unreadable] reactivation of persisting bacteria.This proposal seeks to test the hypothesis that the capacity of[unreadable] Mtb to inhibit infection-induced apoptosis of macrophages is a major pathway of the bacteria to[unreadable] avoid the host?s innate and adaptive immune response. Furthermore it proposes that the[unreadable] discovery of mycobacterial genes involved in the inhibition of host cell apoptosis will lead to new[unreadable] drug targets for resolving persistent bacterial infections and to new improved attenuated vaccine[unreadable] strains. Presently, the capacity of mycobacteria to inhibit macrophage apoptosis has been linked[unreadable] to bacterial virulence based only on correlative data due to the lack of defined bacterial mutants.[unreadable] The AIM 1 of the proposal targets to fill that gap in our knowledge by identifying several[unreadable] mycobacterial genes important for apoptosis inhibition using a unique ?gain-of-function? genetic[unreadable] screen. The success of this approach has been proven by the identification of one anti-apoptotic[unreadable] gene of Mtb, nuoG, but at least two additional genes remain to be identified. AIM 2 proposes to[unreadable] characterize the molecular mechanisms by which nuoG is able to suppress host cell apoptosis.[unreadable] Finally, in AIM 3 the bacterial mutants are used to address the importance of apoptosis inhibition[unreadable] for the bacterial escape from the host?s innate and acquired immune response in[unreadable] immunodeficient and immunocompetent mice, respectively. In addition, the identified anti-apoptotic[unreadable] gene will be deleted in the currently used TB vaccine strain (BCG) and the effect of[unreadable] the mutation on the vaccine potential will be tested in the mouse model of TB. Altogether, the[unreadable] successful completion of the proposed studies would lead to the identification of new TB drug[unreadable] targets and may result in an improved TB vaccine strain.